U.S. patent application number 10/477546 was filed with the patent office on 2010-10-21 for pyrimidine derivatives.
This patent application is currently assigned to GLAXO GROUP LIMITED. Invention is credited to Gianpaolo Bravi, Malcolm Clive Carter, Jennifer Margaret Doughty, Richard Howard Green, Charles David Hartley, Alan Naylor, Martin Pass, Jeremy John Payne, Neil Anthony Pegg.
Application Number | 20100267755 10/477546 |
Document ID | / |
Family ID | 9915323 |
Filed Date | 2010-10-21 |
United States Patent
Application |
20100267755 |
Kind Code |
A1 |
Bravi; Gianpaolo ; et
al. |
October 21, 2010 |
PYRIMIDINE DERIVATIVES
Abstract
The invention provides the compounds of formula (I) ##STR00001##
and pharmaceutically acceptable salts thereof, in which: R.sup.1
and R.sup.2 are independently selected from the group consisting of
H, C.sub.1-6alkyl, C.sub.1-2alkyl substituted by one to five
fluorine atoms, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.4-12bridged cycloalkyl,
A(CR.sup.7R.sup.8).sub.n and B(CR.sup.7R.sup.8).sub.n; R.sup.3 is
selected from the group consisting of C.sub.1-6alkyl, NH.sub.2 and
R.sup.10CONH; R.sup.4 is C.sub.1-2alkyl substituted by one to five
fluorine atoms; R.sup.5 is selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.1-2alkyl substituted with one to five
fluorine atoms, halogen and C.sub.3-10cycloalkylC.sub.0-6alkyl,
with the proviso that when R.sup.6 is H R.sup.5 is not H. R.sup.6
is selected from the group consisting of H, C.sub.1-4alkyl,
C.sub.1-2alkyl substituted with one to five fluorine atoms,
halogen, C.sub.1-4alkoxy, CN, NO.sub.2, C.sub.1-6alkylOCO,
NH.sub.2CO, C.sub.1-6alkylNHCO, NH.sub.2, C.sub.1-6alkylNH,
(C.sub.1-6alkyl).sub.2N, (C.sub.1-6alkyl).sub.2NCO,
C.sub.1-6alkylCONH, NH.sub.2SO.sub.2, C.sub.1-6alkylNHSO.sub.2,
(C.sub.1-6alkyl).sub.2NSO.sub.2, C.sub.1-6alkylSO.sub.2NH,
ArSO.sub.2NH, C.sub.1-6alkylSO.sub.2, ArSO.sub.2,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.3-6alkenyl and
C.sub.3-6alkynyl, with the proviso that when R.sup.5 is H R.sup.6
is not H. R.sup.7 and R.sup.8 are independently selected from H or
C.sub.1-6alkyl; A is an unsubstituted 5- or 6-membered heteroaryl
or an unsubstituted 6-membered aryl, or a 5- or 6-membered
heteroaryl or a 6-membered aryl substituted by one or more R.sup.9;
R.sup.9 is selected from the group consisting of hydroxy, halogen,
C.sub.1-6alkyl, C.sub.1-6alkyl substituted by one more fluorine
atoms, C.sub.1-6alkoxy, C.sub.1-6alkoxy substituted by one or more
F, NH.sub.2SO.sub.2 and C.sub.1-6alkylSO.sub.2; R.sup.10 is
selected from the group consisting of H, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylOC.sub.1-6alkyl, phenyl,
HO.sub.2CC.sub.1-6alkyl, C.sub.1-6alkylOCOC.sub.1-6alkyl,
C.sub.1-6alkylOCO, H.sub.2NC.sub.1-6alkyl,
C.sub.1-6alkylOCONHC.sub.1-6alkyl and
C.sub.1-6alkylCONHC.sub.1-6alkyl; B is selected from the group
consisting of ##STR00002## defines the point of attachment of the
ring; and n is 0 to 4. Compounds of formula (I) are potent and
selective inhibitors of COX-2 and are of use in the treatment of
pain, fever and inflammation of a variety of conditions and
diseases.
Inventors: |
Bravi; Gianpaolo;
(Hertfordshire, GB) ; Carter; Malcolm Clive;
(Hertfordshire, GB) ; Green; Richard Howard;
(Hertfordshire, GB) ; Doughty; Jennifer Margaret;
(Gorham, ME) ; Hartley; Charles David;
(Hertfordshire, GB) ; Naylor; Alan;
(Hertfordshire, GB) ; Pass; Martin;
(Hertfordshire, GB) ; Payne; Jeremy John;
(Hertfordshire, GB) ; Pegg; Neil Anthony;
(Hertfordshire, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;GLOBAL PATENTS
FIVE MOORE DR., PO BOX 13398, MAIL STOP: C.2111F
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Assignee: |
GLAXO GROUP LIMITED
Middlesex
GB
Jennifer Margaret GREEN
Hertfordshire
GB
|
Family ID: |
9915323 |
Appl. No.: |
10/477546 |
Filed: |
May 23, 2002 |
PCT Filed: |
May 23, 2002 |
PCT NO: |
PCT/GB2002/002408 |
371 Date: |
June 23, 2006 |
Current U.S.
Class: |
514/275 ;
544/331; 544/332 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 401/12 20130101; C07D 239/42 20130101; C07D 409/12 20130101;
A61P 29/00 20180101; C07D 405/12 20130101 |
Class at
Publication: |
514/275 ;
544/332; 544/331 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61P 29/00 20060101 A61P029/00; C07D 239/42 20060101
C07D239/42; C07D 403/12 20060101 C07D403/12; C07D 405/12 20060101
C07D405/12; C07D 409/12 20060101 C07D409/12; A61K 31/506 20060101
A61K031/506 |
Foreign Application Data
Date |
Code |
Application Number |
May 25, 2001 |
GB |
0112803.2 |
Claims
1. A compound of formula (I) ##STR00024## or a pharmaceutically
acceptable salt thereof, in which: R.sup.1 and R.sup.2 are
independently selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.1-2alkyl substituted by one to five fluorine
atoms, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.4-12bridged cycloalkyl,
A(CR.sup.7R.sup.8).sub.n and B(CR.sup.7R.sup.8).sub.n; R.sup.3 is
selected from the group consisting of C.sub.1-6alkyl, NH.sub.2 and
R.sup.10CONH; R.sup.4 is C.sub.1-2alkyl substituted by one to five
fluorine atoms; R.sup.5 is selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.1-2alkyl substituted with one to five
fluorine atoms, halogen and C.sub.3-10cycloalkylC.sub.0-6alkyl,
with the proviso that when R.sup.6 is H R.sup.5 is not H. R.sup.6
is selected from the group consisting of H, C.sub.1-4alkyl,
C.sub.1-2alkyl substituted with one to five fluorine atoms,
halogen, C.sub.1-4alkoxy, CN, NO.sub.2, C.sub.1-6alkylOCO,
NH.sub.2CO, C.sub.1-6alkylNHCO, NH.sub.2, C.sub.1-6alkylNH,
(C.sub.1-6alkyl).sub.2N, (C.sub.1-6alkyl).sub.2NCO,
C.sub.1-6alkylCONH, NH.sub.2SO.sub.2, C.sub.1-6alkylNHSO.sub.2,
(C.sub.1-6alkyl).sub.2NSO.sub.2, C.sub.1-6alkylSO.sub.2NH,
ArSO.sub.2NH, C.sub.1-6alkylSO.sub.2, ArSO.sub.2,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.3-6alkenyl and
C.sub.3-6alkynyl, with the proviso that when R.sup.5 is H R.sup.6
is not H. R.sup.7 and R.sup.8 are independently selected from H or
C.sub.1-6alkyl; A is an unsubstituted 5- or 6-membered heteroaryl
or an unsubstituted 6-membered aryl, or a 5- or 6-membered
heteroaryl or a 6-membered aryl substituted by one or more R.sup.9;
R.sup.9 is selected from the group consisting of hydroxy, halogen,
C.sub.1-6alkyl, C.sub.1-6alkyl substituted by one more fluorine
atoms, C.sub.1-6alkoxy, C.sub.1-6alkoxy substituted by one or more
F, NH.sub.2SO.sub.2 and C.sub.1-6alkylSO.sub.2; R.sup.10 is
selected from the group consisting of H, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylOC.sub.1-6alkyl, phenyl,
HO.sub.2CC.sub.1-6alkyl, C.sub.1-6alkylOCOC.sub.1-6alkyl,
C.sub.1-6alkylOCO, H.sub.2C.sub.1-6alkyl,
C.sub.1-6alkylOCONHC.sub.1-6alkyl and
C.sub.1-6alkylCONHC.sub.1-6alkyl; B is selected from the group
consisting of ##STR00025## defines the point of attachment of the
ring; and n is 0 to 4.
2. The compound as claimed in claim 1 wherein R.sup.1 and R.sup.2
are independently selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.1-2alkyl substituted by one to five fluorine
atoms, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.4-12bridged cycloalkyl,
A(CR.sup.7R.sup.8).sub.n and B(CR.sup.7R.sup.8).sub.n; R.sup.3 is
selected from the group consisting of C.sub.1-6alkyl, NH.sub.2 and
R.sup.10CONH; R.sup.4 is C.sub.1-2alkyl substituted by one to five
fluorine atoms; R.sup.5 is selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.1-2alkyl substituted with one to five
fluorine atoms and C.sub.3-10cycloalkylC.sub.0-6alkyl, with the
proviso that when R.sup.6 is H R.sup.5 is not H. R.sup.6 is
selected from the group consisting of H, C.sub.1-4alkyl,
C.sub.1-2alkyl substituted with one to five fluorine atoms, halogen
and C.sub.1-4alkoxy, with the proviso that when R.sup.6 is H
R.sup.5 is not H. R.sup.7 and R.sup.8 are independently selected
from H or C.sub.1-6alkyl; A is an unsubstituted 5- or 6-membered
heteroaryl or an unsubstituted 6-membered aryl, or a 5- or
6-membered heteroaryl or a 6-membered aryl substituted by one or
more R.sup.9; R.sup.9 is selected from the group consisting of
halogen, C.sub.1-6alkyl, C.sub.1-6alkyl substituted by one or more
fluorine atoms, C.sub.1-6alkoxy, C.sub.1-6alkoxy substituted by one
or more F, NH.sub.2 SO.sub.2 and C.sub.1-6alkyl SO.sub.2; R.sup.10
is selected from the group consisting of H, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylOC.sub.1-6alkyl, phenyl,
HO.sub.2CC.sub.1-6alkyl, C.sub.1-6alkylOCOC.sub.1-6alkyl,
C.sub.1-6alkylOCO, H.sub.2C.sub.1-6alkyl,
C.sub.1-6alkylOCONHC.sub.1-6alkyl and
C.sub.1-6alkylCONHC.sub.1-6alkyl; B is selected from the group
consisting of ##STR00026## defines the point of attachment of the
ring; and n is 0 to 4.
3. The compound as claimed in claim 1 wherein R.sup.1 is H.
4. The compound as claimed in claim 1 wherein R.sup.2 is selected
from the group consisting of C.sub.1-6alkyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl (such as C.sub.3-10cycloalkyl or
C.sub.3-7cycloalkylmethyl), A(CR.sup.7R.sup.8).sub.n and
B(CR.sup.7R.sup.8).sub.n.
5. The compound as claimed in claim 1 wherein R.sup.3 is
C.sub.1-6alkyl.
6. The compound as claimed in claim 1 wherein R.sup.4 is CHF.sub.2,
CH.sub.2F or CF.sub.3.
7. The compound as claimed in claim 1 wherein R.sup.5 is H or
C.sub.1-4alkyl, with the proviso that when R.sup.6 is H R.sup.5 is
not H.
8. The compound as claimed in claim 1 wherein R.sup.6 is selected
from the group consisting of H, C.sub.1-2alkyl (e.g. methyl),
CF.sub.3 and C.sub.1-2alkoxy (e.g. methoxy), with the proviso that
when R.sup.5 is H R.sup.6 is not H.
9. The compound as claimed in claim 1 wherein R.sup.7 and R.sup.8
are independently selected from H or methyl.
10. The compound as claimed in claim 1 wherein A is selected from
the group consisting of ##STR00027## and A is unsubstituted or
substituted by one or two R.sup.9.
11. The compound as claimed in claim 1 wherein R.sup.9 is selected
from the group consisting of hydroxy, halogen, C.sub.1-3alkyl,
C.sub.1-2alkyl substituted by one to five fluorine atoms and
C.sub.1-3alkoxy.
12. The compound as claimed in claim 1 wherein R.sup.10 is selected
from the group consisting of C.sub.1-6alkyl (e.g. ethyl), phenyl
and aminomethyl.
13. The compound as claimed in claim 1 wherein B is
##STR00028##
14. The compound as claimed in claim 1 wherein n is 0 to 2.
15. A process for the preparation of a compound as defined in claim
1, which comprises: (A), reacting an amine HNR.sup.1R.sup.2 of
formula (II) or a protected derivative thereof with a compound of
formula (III) ##STR00029## and thereafter and if necessary, (B),
interconverting a compound of formula (I) into another compound of
formula (I); and/or (C), deprotecting a protected derivative of
compound of formula (I).
16. A pharmaceutical composition comprising a compound as defined
in claim 1 in admixture with one or more physiologically acceptable
carriers or excipients.
17. (canceled)
18. A method of treating a subject suffering from a condition which
is mediated by COX-2 which comprises administering to said subject
an effective amount of a compound as defined in claim 1.
19. A method of treating a subject suffering from an inflammatory
disorder, which method comprises administering to said subject an
effective amount of a compound as defined in claim 1.
20-21. (canceled)
22. The method according to claim 18, wherein said subject is a
human.
23. The method according to claim 19, wherein said subject is a
human.
Description
[0001] This invention relates to pyrimidine derivatives, to
processes for their preparation, to pharmaceutical compositions
containing them and to their use in medicine.
[0002] The enzyme cyclooxygenase (COX) has recently been discovered
to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the
originally identified constitutive enzyme while COX-2 is rapidly
and readily inducible by a number of agents including mitogens,
endotoxin, hormones, cytokines and growth factors. Prostaglandins
generated by the action of COX have both physiological and
pathological roles. It is generally believed that COX-1 is largely
responsible for the important physiological functions such as
maintenance of gastrointestinal integrity and renal blood flow. In
contrast the inducible form, COX-2, is believed to be largely
responsible for the pathological effects of prostaglandins where
rapid induction of the enzyme occurs in response to such agents as
inflammatory agents; hormones, growth factors and cytokines. A
selective inhibitor of COX-2 would therefore have
anti-inflammatory, anti-pyretic and analgesic properties, without
the potential side effects associated with inhibition of COX-1. We
have now found a novel group of compounds which are both potent and
selective inhibitors of COX-2.
[0003] The invention thus provides the compounds of formula (I)
##STR00003##
and pharmaceutically acceptable salts thereof, in which:
[0004] R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, C.sub.1-6alkyl, C.sub.1-2alkyl substituted
by one to five fluorine atoms, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.4-12bridged cycloalkyl,
A(CR.sup.7R.sup.8).sub.n and B(CR.sup.7R.sup.8).sub.n;
[0005] R.sup.3 is selected from the group consisting of
C.sub.1-6alkyl, NH.sub.2 and R.sup.10CONH;
[0006] R.sup.4 is C.sub.1-2alkyl substituted by one to five
fluorine atoms;
[0007] R.sup.5 is selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.1-2alkyl substituted with one to five
fluorine atoms, halogen and C.sub.3-10cycloalkylC.sub.0-6alkyl,
with the proviso that when R.sup.6 is H R.sup.5 is not H.
[0008] R.sup.6 is selected from the group consisting of H,
C.sub.1-2alkyl substituted with one to five fluorine atoms,
halogen, C.sub.1-4alkoxy, CN, NO.sub.2, C.sub.1-6alkylOCO,
NH.sub.2CO, C.sub.1-6alkylNHCO, NH.sub.2, C.sub.1-6alkylNH,
(C.sub.1-6alkyl).sub.2N, (C.sub.1-6alkyl).sub.2NCO,
C.sub.1-6alkylCONH, NH.sub.2SO.sub.2, C.sub.1-6alkylNHSO.sub.2,
(C.sub.1-6alkyl).sub.2NSO.sub.2, C.sub.1-6alkylSO.sub.2NH,
ArSO.sub.2NH, C.sub.1-6alkylSO.sub.2, ArSO.sub.2,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.3-6alkenyl and
C.sub.3-4alkynyl, with the proviso that when R.sup.5 is H R.sup.6
is not H.
[0009] R.sup.7 and R.sup.8 are independently selected from H or
C.sub.1-6alkyl;
[0010] A is an unsubstituted 5- or 6-membered heteroaryl or an
unsubstituted 6-membered aryl, or a 5- or 6-membered heteroaryl or
a 6-membered aryl substituted by one or more R.sup.9;
[0011] R.sup.9 is selected from the group consisting of hydroxy,
halogen, C.sub.1-6alkyl, C.sub.1-6alkyl substituted by one more
fluorine atoms, C.sub.1-6alkoxy, C.sub.1-6alkoxy substituted by one
or more F, NH.sub.2SO.sub.2 and C.sub.1-6alkylSO.sub.2;
[0012] R.sup.10 is selected from the group consisting of H,
C.sub.1-6alkoxy, C.sub.1-6alkylOC.sub.1-6alkyl, phenyl,
HO.sub.2CC.sub.1-6alkyl, C.sub.1-6alkylOCO, H.sub.2NC.sub.1-6alkyl,
C.sub.1-6alkylOCONHC.sub.1-6alkyl and
C.sub.1-6alkylCONHC.sub.1-6alkyl;
[0013] B is selected from the group consisting of
##STR00004##
defines the point of attachment of the ring; and
[0014] n is 0 to 4.
[0015] Suitable pharmaceutically acceptable salts include acid
addition salts formed with the amine functionality NR.sup.1R.sup.2.
Pharmaceutically acceptable salts include those described by Berge,
Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts
may be formed from inorganic and organic acids. Representative
examples thereof include maleic, fumaric, benzoic, ascorbic,
pamoic, succinic, bismethylenesalicyclic, methanesulfonic,
p-toluenesulfonic, ethanedisulfonic, acetic, propionic, tartaric,
salicyclic, citric, gluconic, aspartic, stearic, palmitic,
itaconic, glycolic, p-aminobenzoic, glutamic, taurocholic,
benzenesulfonic, hydrochloric, hydrobromic, sulfuric,
cyclohexylsulfamic, phosphoric and nitric acids.
[0016] It will be appreciated that, for pharmaceutical use, the
salts referred to above will be the physiologically acceptable
salts, but other salts may find use, for example in the preparation
of compounds of formula (I) and the physiologically acceptable
salts thereof.
[0017] The term `halogen` is used to represent fluorine, chlorine,
bromine or iodine.
[0018] The term `alkyl` as a group or part of a group means a
straight or branched chain alkyl group, for example a methyl,
ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
[0019] The term 5-membered heteroaryl means a heteroaryl selected
from the following:
##STR00005##
[0020] The term 6-membered heteroaryl means a heteroaryl selected
from:
##STR00006##
[0021] The term 6-membered aryl means:
##STR00007##
[0022] It is to be understood that the present invention
encompasses all isomers of the compounds of formula (I) and their
pharmaceutically acceptable salts, including all geometric,
tautomeric and optical forms, and mixtures thereof (e.g. racemic
mixtures). In particular when the ring B lacks a plane of symmetry
the compounds of formula (I) contain a chiral centre as indicated
therein by the asterisk *. Furthermore, it will be appreciated by
those skilled in the art that when R.sup.4 and R.sup.5 in formula
(I) are different the corresponding compounds contain at least one
chiral centre, by virtue of the asymmetric carbon atom defined
thereby, and that such compounds exist in the form of a pair of
optical isomers (i.e. enantiomers).
[0023] In one aspect the invention provides compounds of formula
(I) and pharmaceutically acceptable salts thereof, in which:
[0024] R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, C.sub.1-6alkyl, C.sub.1-2alkyl substituted
by one to five fluorine atoms, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.4-12bridged cycloalkyl,
A(CR.sup.7R.sup.8).sub.n and B(CR.sup.7R.sup.8).sub.n;
[0025] R.sup.3 is selected from the group consisting of
C.sub.1-6alkyl, NH.sub.2 and R.sup.10CONH;
[0026] R.sup.4 is C.sub.1-2alkyl substituted by one to five
fluorine atoms;
[0027] R.sup.5 is selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.1-2alkyl substituted with one to five
fluorine atoms, and C.sub.3-10cycloalkylC.sub.0-6alkyl, with the
proviso that when R.sup.6 is H R.sup.5 is not H.
[0028] R.sup.6 is selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.1-2alkyl substituted with one to five
fluorine atoms, halogen and C.sub.1-4alkoxy, with the proviso that
when R.sup.6 is H R.sup.6 is not H.
[0029] R.sup.7 and R.sup.8 are independently selected from H or
C.sub.1-6alkyl;
[0030] A is an unsubstituted 5- or 6-membered heteroaryl or an
unsubstituted 6-membered aryl, or a 5- or 6-membered heteroaryl or
a 6-membered aryl substituted by one or more R.sup.9;
[0031] R.sup.9 is selected from the group consisting of halogen,
C.sub.1-6alkyl, C.sub.1-6alkyl substituted by one or more fluorine
atoms, C.sub.1-6alkoxy, C.sub.1-6alkoxy substituted by one or more
F, NH.sub.2 SO.sub.2 and C.sub.1-6alkyl SO.sub.2;
[0032] R.sup.10 is selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkylOC.sub.1-6alkyl,
phenyl, HO.sub.2CC.sub.1-6alkyl, C.sub.1-6alkylOCO,
H.sub.2NC.sub.1-6alkyl, C.sub.1-6alkylOCONHC.sub.1-6alkyl and
C.sub.1-6alkylCONHC.sub.1-6alkyl;
[0033] B is selected from the group consisting of
##STR00008##
defines the point of attachment of the ring; and
[0034] n is 0 to 4.
[0035] In another aspect of the invention R.sup.1 is H,
[0036] In another aspect of the invention R.sup.2 is selected from
the group consisting of C.sub.1-6alkyl, C.sub.1-2alkyl substituted
by one to five fluorine atoms, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.4-12bridged cycloalkyl
and A(CR.sup.7R.sup.8).sub.n.
[0037] In another aspect of the invention R.sup.2 is selected from
the group consisting of C.sub.1-6alkyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl (such as C.sub.3-10cycloalkyl or
C.sub.3-7cycloalkylmethyl), A(CR.sup.7R.sup.8).sub.n, and
B(CR.sup.7R.sup.8).sub.n.
[0038] In another aspect of the invention R.sup.2 is selected from
the group consisting of C.sub.1-6alkyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl (such as C.sub.3-10cycloalkyl or
C.sub.3-7cycloalkylmethyl) and A(CR.sup.7R.sup.8).sub.n.
[0039] Representative examples of R.sup.2 when it is C.sub.1-6alkyl
include n-propyl, n-butyl and s-butyl. Representative examples of
R.sup.2 when it is C.sub.3-10cycloalkylC.sub.0-6alkyl include
cyclohexyl.
[0040] In another aspect of the invention R.sup.3 is
C.sub.1-6alkyl, such as C.sub.1-3alkyl.
[0041] Representative examples of R.sup.3 include methyl.
[0042] In another aspect of the invention R.sup.4 is CHF.sub.2,
CH.sub.2F or CF.sub.3. In another aspect R.sup.4 is CF.sub.3.
[0043] In another aspect of the invention R.sup.5 is H or
C.sub.1-4alkyl, with the proviso that when R.sup.6 is H R.sup.5 is
not H.
[0044] Representative examples of R.sup.5 include H and methyl.
[0045] In another aspect of the invention R.sup.6 is selected from
the group consisting of H, C.sub.1-2alkyl (e.g. methyl), CF.sub.3
and C.sub.1-2alkoxy (e.g. methoxy), with the proviso that when
R.sup.5 is H R.sup.6 is not H.
[0046] In another aspect of the invention one of R.sup.5 and
R.sup.6 is H.
[0047] In another aspect of the invention R.sup.7 and R.sup.8 are
independently selected from H or methyl. In another aspect R.sup.7
and R.sup.8 are both H.
[0048] In another aspect of the invention A is selected from the
group consisting of
##STR00009##
and A is unsubstituted or substituted by one or two R.sup.9.
[0049] In another aspect of the invention A is selected from the
group consisting of
##STR00010##
and A is unsubstituted or substituted by one or two R.sup.9.
[0050] In another aspect of the invention R.sup.9 is selected from
the group consisting of hydroxy, halogen, C.sub.1-3alkyl,
C.sub.1-2alkyl substituted by one to five fluorine atoms and
C.sub.1-3alkoxy.
[0051] Representative examples of R.sup.9 include methyl, methoxy,
fluorine, bromine and hydroxy.
[0052] In another aspect of the invention R.sup.10 is selected from
the group consisting of C.sub.1-6alkyl (e.g. ethyl), phenyl and
aminomethyl.
[0053] In another aspect of the invention B is
##STR00011##
[0054] In another aspect of the invention n is 1 to 4.
[0055] In another aspect of the invention n is 0 to 2 (e.g. 1).
[0056] It is to be understood that the invention covers all
combinations of particular aspects of the invention as described
hereinabove.
[0057] Since the compounds of the present invention, in particular
compounds of formula (I), are intended for use in pharmaceutical
compositions, it will be understood that they are each provided in
substantially pure form, for example at least 50% pure, more
suitably at least 75% pure and preferably at least 95% pure (% are
on a wt/wt basis). Impure preparations of the compound of formula
(I) may be used for preparing the more pure forms used in
pharmaceutical compositions. Although the purity of intermediate
compounds of the present invention is less critical, it will be
readily understood that the substantially pure form is preferred as
for the compounds of formula (I). Preferably, whenever possible,
the compounds of the present invention are available in crystalline
form.
[0058] When some of the compounds of this invention are allowed to
crystallise or are recrysallised from organic solvents, solvent of
recrystallisation may be present in the crystalline product. This
invention includes within its scope such solvates. Similarly, some
of the compounds of this invention may be crystallised or
recrystallised from solvents containing water. In such cases water
of hydration may be formed. This invention includes within its
scope stoichiometric hydrates as well as compounds containing
variable amounts of water that may be produced by processes such as
lyophilisation. In addition, different crystallisation conditions
may lead to the formation of different polymorphic forms of
crystalline products. This invention includes within its scope all
the polymorphic forms of the compounds of formula (I).
[0059] Compounds of the invention are potent and selective
inhibitors of COX-2. This activity is illustrated by their ability
to selectively inhibit COX-2 over COX-1.
[0060] In view of their selective COX-2 inhibitory activity, the
compounds of the present invention are of interest for use in human
and veterinary medicine, particularly in the treatment of the pain
(both chronic and acute), fever and inflammation of a variety of
conditions and diseases mediated by selective inhibition of COX-2.
Such conditions and diseases are well known in the art and include
rheumatic fever; symptoms associated with influenza or other viral
infections, such as the common cold; lower back and neck pain;
headache; toothache; sprains and strains; myositis; sympathetically
maintained pain; synovitis; arthritis, including rheumatoid
arthritis; degenerative joint diseases, including osteoarthritis;
gout and ankylosing spondylitis; tendinitis; bursitis; skin related
conditions, such as psoriasis, eczema, burns and dermatitis;
injuries, such as sports injuries and those arising from surgical
and dental procedures.
[0061] The compounds of the invention are also useful for the
treatment of neuropathic pain. Neuropathic pain syndromes can
develop following neuronal injury and the resulting pain may
persist for months or years, even after the original injury has
healed. Neuronal injury may occur in the peripheral nerves, dorsal
roots, spinal cord or certain regions in the brain. Neuropathic
pain syndromes are traditionally classified according to the
disease or event that precipitated them. Neuropathic pain syndromes
include: diabetic neuropathy; sciatica; non-specific lower back
pain; multiple sclerosis pain; fibromyalgia; HIV-related
neuropathy; neuralgia, such as post-herpetic neuralgia and
trigeminal neuralgia; and pain resulting from physical trauma,
amputation, cancer, toxins or chronic inflammatory conditions.
These conditions are difficult to treat and although several drugs
are known to have limited efficacy, complete pain control is rarely
achieved. The symptoms of neuropathic pain are incredibly
heterogeneous and are often described as spontaneous shooting and
lancinating pain, or ongoing, burning pain. In addition, there is
pain associated with normally non-painful sensations such as "pins
and needles" (paraesthesias and dysesthesias), increased
sensitivity to touch (hyperesthesia), painful sensation following
innocuous stimulation (dynamic, static or thermal allodynia),
increased sensitivity to noxious stimuli (thermal, cold, mechanical
hyperalgesia), continuing pain sensation after removal of the
stimulation (hyperpathia) or an absence of or deficit in selective
sensory pathways (hypoalgesia).
[0062] The compounds of the invention are also useful for the
treatment of other conditions mediated by selective inhibition of
COX-2.
[0063] For example, the compounds of the invention inhibit cellular
and neoplastic transformation and metastatic tumour growth and
hence are useful in the treatment of certain cancerous diseases,
such as colonic cancer and prostate cancer. The compounds of the
invention are also useful in reducing the number of adenomatous
colorectal polyps and thus reduce the risk of developing colon
cancer. The compounds of the invention are also useful in the
treatment of cancer associated with overexpression of HER-2/neu, in
particular breast cancer.
[0064] Compounds of the invention also prevent neuronal injury by
inhibiting the generation of neuronal free radicals (and hence
oxidative stress) and therefore are of use in the treatment of
stroke; epilepsy; and epileptic seizures (including grand mal,
petit mal, myoclonic epilepsy and partial seizures).
[0065] Compounds of the invention also inhibit prostanoid-induced
smooth muscle contraction and hence are of use in the treatment of
dysmenorrhoea and premature labour.
[0066] Compounds of the invention are also useful in the treatment
of liver disease, such as inflammatory liver disease, for example
chronic viral hepatitis B, chronic viral hepatitis C, alcoholic
liver injury, primary biliary cirrhosis, autoimmune hepatitis,
nonalcoholic steatohepatitis and liver transplant rejection.
[0067] Compounds of the invention inhibit inflammatory processes
and therefore are of use in the treatment of asthma, allergic
rhinitis and respiratory distress syndrome; gastrointestinal
conditions such as inflammatory bowel disease, Crohn's disease,
gastritis, irritable bowel syndrome and ulcerative colitis; and the
inflammation in such diseases as vascular disease, migraine,
periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's
disease, sclerodoma, type I diabetes, myasthenia gravis, multiple
sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome,
polymyositis, gingivitis, conjunctivitis and myocardial
ischemia.
[0068] Compounds of the invention are also useful in the treatment
of ophthalmic diseases such as retinitis, retinopathies, uveitis
and of acute injury to the eye tissue.
[0069] Compounds of the invention are also useful for the treatment
of cognitive disorders such as dementia, particularly degenerative
dementia (including senile dementia, Alzheimer's disease, Pick's
disease, Huntington's chorea, Parkinson's disease and
Creutzfeldt-Jakob disease), and vascular dementia (including
multi-infarct dementia), as well as dementia associated with
intracranial space occupying lesions, trauma, infections and
related conditions (including HIV infection), metabolism, toxins,
anoxia and vitamin deficiency; and mild cognitive impairment
associated with ageing, particularly Age Associated Memory
Impairment.
[0070] Compounds of the invention are also useful in the treatment
of disorders ameliorated by a gastroprokinetic agent. Disorders
ameliorated by gastroprokinetic agents include ileus, for example
post-operative ileus and ileus during sepsis; gastroesophageal
reflux disease (GORD, or its synonym GERD); gastroparesis, such as
diabetic gastroparesis; and other functional bowel disorders, such
as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain
(NCCP).
[0071] According to a further aspect of the invention, we provide a
compound of formula (I) or a pharmaceutically acceptable salt
thereof for use in human or veterinary medicine.
[0072] According to another aspect of the invention, we provide a
compound of formula (I) or a pharmaceutically acceptable salt
thereof for use in the treatment of a condition which is mediated
by COX-2.
[0073] According to a further aspect of the invention, we provide a
method of treating a human or animal subject suffering from a
condition which is mediated by COX-2 which comprises administering
to said subject an effective amount of a compound of formula (I) or
a pharmaceutically acceptable salt.
[0074] According to a further aspect of the invention, we provide a
method of treating a human or animal subject suffering from an
inflammatory disorder, which method comprises administering to said
subject an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[0075] According to another aspect of the invention, we provide the
use of a compound of formula (I) or a pharmaceutically acceptable
salt thereof for the manufacture of a therapeutic agent for the
treatment of a condition which is mediated by COX-2.
[0076] According to another aspect of the invention, we provide the
use of a compound of formula (I) or a pharmaceutically acceptable
salt thereof for the manufacture of a therapeutic agent for the
treatment of an inflammatory disorder.
[0077] It is to be understood that reference to treatment includes
both treatment of established symptoms and prophylactic treatment,
unless explicitly stated otherwise.
[0078] It will be appreciated that the compounds of the invention
may advantageously be used in conjunction with one or more other
therapeutic agents. Examples of suitable agents for adjunctive
therapy include a 5HT.sub.1 agonist, such as a triptan (e.g.
sumatriptan or naratriptan); an adenosine A1 agonist; an EP ligand;
an NMDA modulator, such as a glycine antagonist; a sodium channel
blocker (e.g. lamotrigine); a substance P antagonist (e.g. an
NK.sub.1 antagonist); a cannabinoid; acetaminophen or phenacetin; a
5-lipoxygenase inhibitor; a leukotriene receptor antagonist; a
DMARD (e.g. methotrexate); gabapentin and related compounds; a
tricyclic antidepressant (e.g. amitryptilline); a neurone
stabilising antiepileptic drug; a mono-aminergic uptake inhibitor
(e.g. venlafaxine); a matrix metalloproteinase inhibitor; a nitric
oxide synthase (NOS) inhibitor, such as an iNOS or an nNOS
inhibitor; an inhibitor of the release, or action, of tumour
necrosis factor .alpha.; an antibody therapy, such as a monoclonal
antibody therapy; an antiviral agent, such as a nucleoside
inhibitor (e.g. lamivudine) or an immune system modulator (e.g.
interferon); an opioid analgesic; a local anaesthetic; a stimulant,
including caffeine; an H.sub.2-antagonist (e.g. ranitidine); a
proton pump inhibitor (e.g. omeprazole); an antacid (e.g. aluminium
or magnesium hydroxide; an antiflatulent (e.g. simethicone); a
decongestant (e.g. phenylephrine, phenylpropanolamine,
pseudoephedrine, oxymetazoline, epinephrine, naphazoline,
xylometazoline, propylhexedrine, or levo-desoxyephedrine); an
antitussive (e.g. codeine, hydrocodone, carmiphen, carbetapentane,
or dextramethorphan); a diuretic; or a sedating or non-sedating
antihistamine. It is to be understood that the present invention
covers the use of a compound of formula (I) or a pharmaceutically
acceptable salt thereof in combination with one or more other
therapeutic agents.
[0079] The compounds of formula (I) and their pharmaceutically
acceptable salts are conveniently administered in the form of
pharmaceutical compositions. Thus, in another aspect of the
invention, we provide a pharmaceutical composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt
thereof adapted for use in human or veterinary medicine. Such
compositions may conveniently be presented for use in conventional
manner in admixture with one or more physiologically acceptable
carriers or excipients.
[0080] The compounds of formula (I) and their pharmaceutically
acceptable salts may be formulated for administration in any
suitable manner. They may, for example, be formulated for topical
administration or administration by inhalation or, more preferably,
for oral, transdermal or parenteral administration. The
pharmaceutical composition may be in a form such that it can effect
controlled release of the compounds of formula (I) and their
pharmaceutically acceptable salts.
[0081] For oral administration, the pharmaceutical composition may
take the form of, for example, tablets (including sub-lingual
tablets), capsules, powders, solutions, syrups or suspensions
prepared by conventional means with acceptable excipients.
[0082] For transdermal administration, the pharmaceutical
composition may be given in the form of a transdermal patch, such
as a transdermal iontophoretic patch.
[0083] For parenteral administration, the pharmaceutical
composition may be given as an injection or a continuous infusion
(e.g. intravenously, intravascularly or subcutaneously). The
compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles and may contain formulatory
agents such as suspending, stabilising and/or dispersing agents.
For administration by injection these may take the form of a unit
dose presentation or as a multidose presentation preferably with an
added preservative.
[0084] Alternatively for parenteral administration the active
ingredient may be in powder form for reconstitution with a suitable
vehicle.
[0085] The compounds of the invention may also be formulated as a
depot preparation. Such long acting formulations may be
administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds of the invention may be formulated with suitable
polymeric or hydrophobic materials (for example as an emulsion in
an acceptable oil) or ion exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt.
[0086] As stated above, the compounds of the invention may also be
used in combination with other therapeutic agents. The invention
thus provides, in a further aspect, a combination comprising a
compound of formula (I) or a pharmaceutically acceptable salt
thereof together with a further therapeutic agent.
[0087] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical formulation and
thus pharmaceutical formulations comprising a combination as
defined above together with a pharmaceutically acceptable carrier
or excipient comprise a further aspect of the invention. The
individual components of such combinations may be administered
either sequentially or simultaneously in separate or combined
pharmaceutical formulations.
[0088] When a compound of formula (I) or a pharmaceutically
acceptable salt thereof is used in combination with a second
therapeutic agent active against the same disease state the dose of
each compound may differ from that when the compound is used alone.
Appropriate doses will be readily appreciated by those skilled in
the art.
[0089] A proposed daily dosage of a compound of formula (I) for the
treatment of man is 0.01 mg/kg to 500 mg/kg, such as 0.05 mg/kg to
100 mg/kg, e.g. 0.1 mg/kg to 50 mg/kg, which may be conveniently
administered in 1 to 4 doses. The precise dose employed will depend
on the age and condition of the patient and on the route of
administration. Thus, for example, a daily dose of 0.25 mg/kg to 10
mg/kg may be suitable for systemic administration.
[0090] Compounds of formula (I) and pharmaceutically acceptable
salts thereof may be prepared by any method known in the art for
the preparation of compounds of analogous structure.
[0091] Compounds of formula (I) and pharmaceutically acceptable
salts thereof may be prepared by a process which comprises:
[0092] reacting an amine R.sup.1R.sup.2NH of formula (II) or a
protected derivative thereof with a compound of formula (III)
##STR00012##
and thereafter and if necessary,
[0093] interconverting a compound of formula (I) into another
compound of formula (I); and/or
[0094] deprotecting a protected derivative of compound of formula
(I).
[0095] The overall synthesis of a compound of formula (I) is shown
in Schemes 1 to 3 below.
[0096] In Scheme 1, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6
are as defined in formula (I) above, R.sup.3 is C.sub.1-6alkyl;
alkyl is a straight or branched chain alkyl group, for example
methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl
group.
##STR00013##
[0097] In Scheme 2, R.sup.1, R.sup.2, R.sup.4 and R.sup.6 are as
defined in formula (I) above, R.sup.3 is C.sub.1-6alkyl, and
R.sup.5 is C.sub.1-4alkyl or C.sub.3-10cycloalkylC.sub.0-6alkyl;
alkyl is a straight or branched chain alkyl group, for example
methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl
group.
##STR00014##
[0098] In Scheme 3, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as
defined in formula (I) above, R.sup.3 is C.sub.1-6alkyl, and
R.sup.6 is halogen or C.sub.1-4alkoxy; alkyl is a straight or
branched chain alkyl group, for example methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl or t-butyl group; X is a suitable
leaving group such as halogen; and CDI is
1,1'-carbonyldiimidazole.
##STR00015##
[0099] Referring to Schemes 1, 2 and 3, the treatment of compounds
of formula (III) with an amine of formula (II) is conveniently
carried out in a solvent, such as nitrile (e.g. methylnitrile) and
at elevated temperature (e.g. from about 50.degree. C. to reflux).
An excess of the amine may be used in place of the solvent.
[0100] Alternatively, the treatment of compounds of formula (III)
with an amine of formula (II) is conveniently carried out in a
solvent, such as a tertiary amine (e.g. NMP), and at between
ambient and elevated temperature (e.g. ambient temperature). Use
of, for example, NMP as solvent has the advantage that after
completion of the reaction the desired compound of formula (I) may
be precipitated from the reaction mixture by the addition of water,
allowing for easier isolation and purification.
[0101] Conveniently the oxidation shown in Schemes 1, 2 and 3 is
effected using a monopersulfate compound, such as potassium
peroxymonosulfate (known as Oxone.TM.) and the reaction is carried
out in a solvent, such as an aqueous alcohol, (e.g. aqueous
methanol), and at between -78.degree. C. and ambient
temperature.
[0102] Alternatively, the oxidation shown in Schemes 1, 2 and 3 may
be effected using hydrogen peroxide in the presence of catalytic
sodium tungstate dihydrate. The reaction may be carried out in a
solvent such as acetic acid and at between ambient temperature and
reflux (e.g. 50.degree. C.).
[0103] Referring to Schemes 1, 2 and 3, the cyclisation of diones
of formula (VI) to give the corresponding pyrimidines of formula
(IV) is conveniently carried out employing a thioronium salt such
as a 2-methyl-2-thiopseudourea sulfate and under reflux.
[0104] Referring to Scheme 1, acid chlorides of formula (VIII) are
either known compounds or may be prepared by conventional
chemistry.
[0105] Compounds of formula (VII) in Schemes 1, 2 and 3 are either
known compounds or may be prepared by conventional chemistry.
[0106] It will be appreciated by those skilled in the art that
certain of the procedures described in Schemes 1, 2 and 3 for the
preparation of compounds of formula (I) or intermediates thereto
may not be applicable to some of the possible substituents.
[0107] It will be further appreciated by those skilled in the art
that it may be necessary or desirable to carry out the
transformations described in Schemes 1, 2 and 3 in a different
order from that described, or to modify one or more of the
transformations, to provide the desired compound of formula
(I).
[0108] In one variation of Schemes 1, 2 and 3, compounds of formula
(III) wherein R.sup.3 is C.sub.1-6alkyl or NH.sub.2 may be prepared
by oxidising a compound of formula (IV)A:
##STR00016##
under oxidation conditions described hereinabove. Compounds of
formula (IV)A may be prepared according to the general procedures
of Schemes 1, 2 and 3 by employing sulphonyl derivatives in place
of the corresponding sulfide compounds.
[0109] It will be appreciated by those skilled in the art that
compounds of formula (I) may be prepared by interconversion,
utilising other compounds of formula (I) as precursors. Suitable
interconversions, such as alkylations, are well known to those
skilled in the art and are described in many standard organic
chemistry texts, such as `Advanced Organic Chemistry` by Jerry
March, fourth edition (Wiley, 1992), incorporated herein by
reference. For example, compounds of formula (I) wherein R.sup.1 is
C.sub.1-6alkyl, C.sub.1-2alkyl substituted by one to five fluorine
atoms, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-10cycloalkylC.sub.0-6alkyl, C.sub.4-12bridged cycloalkane,
(CR.sup.4R.sup.5).sub.nA (with the proviso that n is not zero) and
(CR.sup.4R.sup.5).sub.nB may be prepared by alkylating the
corresponding compound of formula (I) wherein R.sup.1 is H.
[0110] Acylation of compounds of formula (I) wherein R.sup.3 is
NH.sub.2, to provide corresponding acylated benzenesulphonamide
derivatives, may be carried out by conventional means, for example
by employing conventional acylating agents such as those described
in `Advanced Organic Chemistry`, pp 417-424, incorporated herein by
reference.
[0111] As will be appreciated by those skilled in the art it may be
necessary or desirable at any stage in the synthesis of compounds
of formula (I) to protect one or more sensitive groups in the
molecule so as to prevent undesirable side reactions.
[0112] The protecting groups used in the preparation of compounds
of formula (I) may be used in conventional manner. See, for
example, those described in `Protective Groups in Organic
Synthesis` by Theodora W Green and Peter G M Wuts, second edition,
(John Wiley and Sons, 1991), incorporated herein by reference,
which also describes methods for the removal of such groups.
[0113] Amines of formula (II) are either known compounds or may be
prepared by literature methods, such as those described in
`Comprehensive Organic Transformations: a guide to functional group
preparations` by Richard Larock (VCH, 1989), incorporated herein by
reference.
[0114] Thioronium salts of formula (V) are either known compounds
or may be prepared by literature methods, such as those described
in A H Owens et al, Eur J Med Chem, 1988, 23(3), 295-300,
incorporated herein by reference.
[0115] Certain intermediates described above are novel compounds,
and it is to be understood that all novel intermediates herein form
further aspects of the present invention. Compounds of formulae
(III) and (IV) are key intermediates and represent a particular
aspect of the present invention.
[0116] Conveniently, compounds of the invention are isolated
following work-up in the form of the free base. Pharmaceutically
acceptable acid addition salts of the compounds of the invention
may be prepared using conventional means.
[0117] Solvates (e.g. hydrates) of a compound of the invention may
be formed during the work-up procedure of one of the aforementioned
process steps.
[0118] The Intermediates and Examples which follow illustrate the
invention but do not limit the invention in any way. All
temperatures are in .degree. C.
Intermediate 1
1-[4-(Methylthio)phenyl]propan-1-one
[0119] A solution of 4-(methylthio)benzonitrile (7.46 g, 50 mmol)
in anhydrous tetrahydrofuran (50 mL) was added dropwise (over a
period of 0.5 hours) to a solution of ethyl magnesium bromide (100
mL, 1.0 M solution in tetrahydrofuran) with stirring, under a
nitrogen atmosphere. The resultant reaction mixture was stirred for
2 hours, before being heated to reflux for a period of 5 hours. The
reaction mixture was then stirred overnight at ambient room
temperature.
[0120] The reaction mixture was cooled in an ice-bath to a
temperature of 0.degree. C. before 2M sulphuric acid (15 mL) was
added dropwise (the temperature being maintained below 20.degree.
C.). The resultant thick yellow suspension was filtered under vacuo
and the resultant filter cake was washed generously with ethyl
acetate. The filtrate containing the product was then washed with
2M sulphuric acid, followed by saturated sodium hydrogen carbonate
and then finally with water. The organic phase was separated and
dried over anhydrous magnesium. The magnesium sulphate was filtered
off under suction and the filtrate was evaporated under vacuo to
yield the desired product as a solid (8.3 g, 92%).
C.sub.10H.sub.12SO (Calculated 180.2). Found MH+ 181.
Intermediate 2
4,4,4-Trifluoro-2-methyl-1-[4-(methylthio)phenyl]butane-1,3-dione
[0121] A solution of 1-[4-(methylthio)phenyl]propan-1-one (4.0 g,
22 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to a
temperature of -78.degree. C. under a nitrogen atmosphere. To this
solution was added gradually a solution of sodium
bis(trimethylsilylamide) (24 mL, 24 mmol, 1.0M solution in
tetrahydrofuran) whilst maintaining the temperature at -78.degree.
C. On completion of the addition of the sodium
bis(trimethylsilylamide) the resultant reaction mixture was stirred
for a further 45 minutes at a temperature of -78.degree. C., before
the reaction mixture was allowed to warm to a temperature of
-20.degree. C. (briefly). The reaction mixture was then cooled to a
temperature of -78.degree. C. To the resultant sodio-salt of
1-[4-(methylthio)phenyl]propan-1-one was added a solution of
1-(trifluoroacetyl) imidazole (2.8 mL, 25 mmol) in anhydrous
tetrahydrofuran (10 mL). On completion of the addition of the
solution of 1-(trifluoroacetyl) imidazole, the reaction mixture was
stirred for a further 5 minutes, before the reaction mixture was
allowed to warm to ambient room temperature. The reaction mixture
was then stirred overnight at ambient room temperature. The
reaction mixture was carefully quenched with water and acidified
with 1M hydrochloric acid. The reaction mixture was then extracted
into ethyl acetate. The organic phase was separated and combined
before being washed with 1 M hydrochloric acid, followed by water.
The organic phase was separated and dried over anhydrous magnesium
sulphate. The magnesium sulphate was then filtered off under
suction and the filtrate evaporated to yield the crude product as
an oil. The crude product was purified via silica gel
chromatography eluting with ethyl acetate:cyclohexane (1:19). This
gave the desired product as a colourless solid (2.3 g, 38%).
[0122] C.sub.12H.sub.11O.sub.2F.sub.3S (Calculated 276.3). Found
MH+ 277.
Intermediate 3
5-Methyl-2-(methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl)pyrimi-
dine
[0123] A mixture of
4,4,4-trifluoro-2-methyl-1-[4-(methylthio)phenyl]butane-1,3-dione
(2.2 g, 8.0 mmol), 2-methyl-2-thiopseudourea sulphate (2.7 g, 9.6
mmol) and anhydrous sodium acetate (1.3 g, 16 mmol) in glacial
acetic acid (10 mL) was heated to reflux, overnight, under a
nitrogen atmosphere. The reaction mixture was diluted with water
and the product was extracted into ethyl acetate. The organic phase
was separated and dried over anhydrous magnesium sulphate. The
magnesium sulphate was filtered off under suction and the filtrate
was then evaporated under vacuo to give the crude product. The
product was purified via silica gel chromatography, eluting with
cyclohexane. The desired product was obtained as a colourless solid
(2.2 g, 83%).
[0124] C.sub.14H.sub.13N.sub.2F.sub.3S.sub.2 (Calculated 330.4).
Found MH+ 331.
Intermediate 4
5-Methyl-2-(methylsulfonyl)-4-[4-(methylsulphonyl)phenyl]-6-(trifluorometh-
yl)pyrimidine
[0125] To a solution of
5-methyl-2-(methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl)pyrim-
idine (2.2 g, 6.6 mmol) in methanol (150 mL) was added potassium
peroxymonosulphate (OXONE) (18 g, 29 mmol) followed by water (30
mL). The resultant reaction mixture was stirred overnight (under a
nitrogen atmosphere) at ambient room temperature. The reaction
mixture was filtered under suction to remove suspended colourless
solid and the filtrate was then evaporated under vacuo to give the
product. The product was dissolved in dichloromethane and dried by
passing the dichloromethane solution through a hydrophobic frit.
The dichloromethane was removed by evaporation under vacuo to yield
the desired product as a crystalline colourless solid (2.6 g,
100%).
[0126] C.sub.14H.sub.13F.sub.3N.sub.2O.sub.4S.sub.2 (Calculated
394.4). Found MH+ 395 (MNH4+ 412).
EXAMPLE 1
N-benzyl-5-methyl-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidi-
n-2-amine
[0127] To a solution of
5-methyl-2-(methylsulfonyl)-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromet-
hyl)pyrimidine (20 mg, 0.051 mmol) in 1-methyl-2-pyrrolidinone (2.0
mL) was added benzylamine (28 .mu.L, 0.25 mmol). The resultant
solution was stirred overnight at ambient room temperature. The
reaction mixture was diluted with water (5 mL) before being applied
to a reverse phase column (SPE cartridge C 18 Octadecyl, 10 g, 60
mL) eluting with water (initially) to remove
1-methyl-2-pyrrolidinone, followed by acetonitrile to elute the
crude product. The product was purified by silica gel
chromatography eluting with dichloromethane, followed by ethyl
acetate:cyclohexane (1:1 v/v). This afforded the title compound as
a colourless oil that solidified to a colourless solid on standing
(12.8 mg, 59.9%).
[0128] C.sub.20H.sub.18F.sub.3N.sub.3O.sub.2S (Calculated 421.4).
Found MH+=422.
EXAMPLE 2
N-isobutyl-5-methyl-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimi-
din-2-amine
[0129] To a solution of
5-methyl-2-(methylsulfonyl)-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromet-
hyl)pyrimidine (20 mg, 0.051 mmol) in acetonitrile (5.0 mL) was
added isobutylamine (25 .mu.L, 0.25 mmol). The resultant solution
was heated overnight at a temperature of 80.degree. C. The reaction
mixture was allowed to cool before the solvent was removed by
evaporation under vacuo. The resultant oil was purified by silica
gel chromatography (SPE cartridge SiO.sub.2, 10 g, 60 mL) eluting
with dichloromethane, followed by ethyl acetate:cyclohexane (1:1
v/v). This afforded the title compound as a colourless solid (15.6
mg, 79%). C.sub.17H.sub.20F.sub.3N.sub.3O.sub.2S (Calculated
387.4). Found MH+=388.
[0130] Examples 3 to 15 as shown in Table 1 that follows, were
prepared in the manner described for Examples 1 and 2. [0131] an
open bracket, (, is used to mark the bond between the substituent
and the nitrogen atom to which it is attached.
TABLE-US-00001 [0131] TABLE 1 ##STR00017## MS Ex R.sup.1 R.sup.2
R.sup.3 R.sup.4 R.sup.5 R.sup.6 (MH+) 3 H 2-hydroxybenzyl CH.sub.3
CF.sub.3 CH.sub.3 H 438 4 H ##STR00018## CH.sub.3 CF.sub.3 CH.sub.3
H 428 5 H 4-methylbenzyl CH.sub.3 CF.sub.3 CH.sub.3 H 436 6 H
cyclohexyl CH.sub.3 CF.sub.3 CH.sub.3 H 414 7 H ##STR00019##
CH.sub.3 CF.sub.3 CH.sub.3 H 430 8 H n-propyl CH.sub.3 CF.sub.3
CH.sub.3 H 374 9 H ##STR00020## CH.sub.3 CF.sub.3 CH.sub.3 H 423 10
H ##STR00021## CH.sub.3 CF.sub.3 CH.sub.3 H 437 11 H n-butyl
CH.sub.3 CF.sub.3 CH.sub.3 H 388 12 H ##STR00022## CH.sub.3
CF.sub.3 CH.sub.3 H 426 13 H ##STR00023## CH.sub.3 CF.sub.3
CH.sub.3 H 412 14 H 4-methoxybenzyl CH.sub.3 CF.sub.3 CH.sub.3 H
452 15 H 4-fluorobenzyl CH.sub.3 CF.sub.3 CH.sub.3 H 440
[0132] Biological Data
[0133] Inhibitory activity against microsomal h-COX2 was assessed
against a microsomal preparation from baculovirus infected SF9
cells. An aliquot of microsomal preparation was thawed slowly on
ice and a 1/40,000 dilution prepared from it into the assay buffer
(sterile water, degassed with argon containing 100 mM HEPES (pH
7.4), 10 mM EDTA (pH7.4), 1 mM phenol, 1 mM reduced glutathione, 20
mg/ml gelatin and 0.001 mM Hematin). Once diluted the enzyme
solution was then sonicated for 5 seconds (Branson sonicator,
setting 4, 1 cm tip) to ensure a homogeneous suspension. 155 .mu.l
enzyme solution was then added to each well of a 96-well microtitre
plate containing either 5 .mu.l test compound (40.times. required
test concentration) or 5 .mu.l DMSO for controls. Plates were then
mixed and incubated at room temperature for 1 hour. Following the
incubation period, 40 .mu.l of 0.5 .mu.M arachidonic acid was added
to each well to give a final concentration of 0.1 .mu.M. Plates
were then mixed and incubated for exactly 10 minutes (room
temperature) prior to addition of 25 .mu.l 1M HCl (hydrochloric
acid) to each well to stop the reaction. 25 .mu.l of 1M NaOH
(sodium hydroxide) was then added to each well to neutralise the
solution prior to determination of PGE.sub.2 levels by enzyme
immunoassay (EIA). Results are expressed as % inhibition of PGE2
release by the compound compared to solvent control at 10
micromolar concentration.
TABLE-US-00002 Example No. COX-2% inhibition COX-2 IC50 (.mu.M) 1
61 1.3 2 6.6 3 2.5 4 0.56 5 15.3 6 2.3 7 >100 8 26.7 9 >98.6
10 71.2 11 43 6.3 12 11 13 43 14 23 15 35
* * * * *